Novel diagnostic and stratification tools for septic shock

感染性休克的新型诊断和分层工具

• 批准号: 8970115
• 负责人: HECTOR R. WONG
• 金额: $ 30.07万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970115
• 关键词: APACHE II; APACHE III; Address; Adult; Age; Biological; Biological Markers; Blood; Blood Transfusion; Caring; Catheters; Child; Childhood; Clinical; Clinical Trials; Collaborations; Conduct Clinical Trials; Country; Coupled; Data; Diagnosis; Disease; Enrollment; Failure; Foundations; Funding; Future; Goals; Grant; Heterogeneity; Hospital Mortality; Intervention; Measures; Modeling; Organ failure; Outcome; Pathway interactions; Patient Selection; Patients; Plasma; Population Study; Probability; Procedures; Proteins; Protocols documentation; Public Health; Relative (related person); Research; Research Personnel; Resuscitation; Risk; Sample Size; Sampling; Sepsis; Septic Shock; Stratification; Study Subject; Syndrome; System; Technology; Testing; Time; United States National Institutes of Health; Vasopressins; Venous; base; design; improved; innovation; meetings; mortality; novel; novel diagnostics; novel strategies; programs; public health relevance; repository; standard care; three-arm study; tool; transcriptomics; translational study; treatment as usual; trial design

 DESCRIPTION (provided by applicant): Septic shock continues to be a worldwide public health problem in both adults and children. Septic shock is a heterogeneous syndrome, not a discrete disease entity. Baseline mortality risk is widely variable, making it a major confounder for the conduct of interventional clinical trials. Current trial designs include patients with low baseline mortality risk who are unlikely to benefit from novel interventions beyond standard care, as well as patients having an extremely high baseline mortality risk who may be beyond salvage even with novel interventions. This can dilute the effect size for an experimental intervention that has benefit for patients between these extremes who have a significant, but modifiable mortality risk. Thus, an important and unmet clinical gap in the field is the lack of a robust stratification tool specific for septic shock. This proposal seeks to directly address this gap. We have derived and validated the Pediatric Sepsis Biomarker Risk Model (PERSEVERE). The biomarkers included in PERSEVERE were selected objectively based on extensive, discovery-oriented transcriptomic studies. Of note, the biomarkers are proteins measured in the blood compartment and are measured at the time of meeting clinical criteria for septic shock. We recently derived and validated the risk stratification model for adults using the same approach in 881 subjects from three different countries. The Adult Septic Shock Information and Stratification Technology (ASSIST) outperform both APACHE II and III. Consistent with our preliminary data, we propose that one application of ASSIST is to better inform the selection of patients for interventional clinical trials. In this competitive revision, we will test this concep by conducting a post hoc, risk-stratified analysis of the Protocolized Care for Early Septic Shock (ProCESS) Trial. The ProCESS Trial randomly allocated 1,341 adults with septic shock into one of three early resuscitation strategies: protocol-based early goal-directed therapy (EGDT); protocol-based standard therapy that did not require placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. An important component of the ProCESS trial was the banking of biological samples at multiple time points, coupled with extensive clinical annotations. Accordingly, the ProCESS trial has generated one the most extensive, contemporary clinical and biological repositories of adult septic shock available. In collaboration with the ProCESS Investigators, we will test the hypothesis that the potential benefits of protocolized care in patients with septic shock, relative to usual care, are dependent on baseline mortality risk as estimated by ASSIST. This focused, competitive revision represents a first step toward bridging two innovative, NIH-funded, sepsis research programs to address major gaps in the field. This highly focused effort will provide the foundation for more extensive collaborations in the near future. The major deliverable of this Aim is a direct test of the concept that baseline mortality risk-based selection is an effective means of conducting interventional clinical trials for septic shock.

 描述（由申请人提供）：感染性休克仍然是成人和儿童的全球公共卫生问题。感染性休克是一种异质性综合征，而不是一个独立的疾病实体。基线死亡风险变化很大，使其成为进行干预性临床试验的主要混杂因素。目前的试验设计包括基线死亡风险低的患者，这些患者不太可能从标准治疗以外的新型干预措施中获益，以及基线死亡风险极高的患者，即使采用新型干预措施也可能无法挽救。这可能会稀释实验性干预的效应量，而实验性干预对这些极端之间具有显著但可改变的死亡风险的患者有益。因此，该领域的一个重要且未得到满足的临床差距是缺乏针对感染性休克的稳健分层工具。这项建议旨在直接解决这一差距。我们已经推导并验证了儿科败血症生物标志物风险模型（PERSEVERE）。PERSEVERE中包含的生物标志物是基于广泛的、以发现为导向的转录组学研究客观选择的。值得注意的是，生物标志物是在血液室中测量的蛋白质，并且在满足感染性休克的临床标准时测量。我们最近在来自三个不同国家的881名受试者中使用相同的方法推导并验证了成人的风险分层模型。成人感染性休克信息和分层技术（ASSIST）优于APACHE II和III。与我们的初步数据一致，我们建议ASSIST的一个应用是更好地为介入性临床试验选择患者提供信息。在这一竞争性修订中，我们将通过对早期感染性休克的方案化治疗（ProCESS）试验进行事后风险分层分析来检验这一概念。ProCESS试验将1，341名感染性休克成人随机分配到三种早期复苏策略之一中：基于协议的早期目标导向治疗（EGDT）;基于协议的标准治疗，不需要放置中心静脉导管，给予正性肌力药物或输血;或常规护理。ProCESS试验的一个重要组成部分是在多个时间点建立生物样本库，以及广泛的临床注释。因此，ProCESS试验产生了一个最广泛的，当代的成人感染性休克的临床和生物学知识库。与ProCESS研究者合作，我们将检验以下假设：相对于常规治疗，脓毒性休克患者的方案化治疗的潜在获益取决于ASSIST估计的基线死亡风险。这一重点突出的竞争性修订代表了弥合两个创新的、NIH资助的脓毒症研究项目的第一步，以解决该领域的主要差距。这一高度集中的努力将为不久的将来更广泛的合作奠定基础。该目标的主要可交付成果是对以下概念的直接测试：基于基线死亡率风险的选择是进行脓毒性休克干预性临床试验的有效手段。